This invention relates to a device for use in biomedical research, and, in particular, to a system for conducting tests and monitoring conscious and freely-moving animals.
Working with living animals is a requirement for important biomedical research techniques, such as infusion, in vivo microdialysis, in vivo ultrafiltration, in vivo electrochemistry, and electrocardiology. All of these techniques study the performance of living organs, such as the brain, heart, circulatory system, muscles, etc. These techniques also require connections between one or more external devices and one or more sensors or implants in the animal's body. Examples of devices include syringe pumps, fraction collectors, electrometers, vacuum sources, light sources, and potentiostats. Examples of implants include infusion cannulae, ultrafiltration probes, microdialysis probes, and electrodes.
U.S. Pat. No. 6,062,224 discloses an apparatus and a method for conducting automated blood sampling (ABS), the teachings of which are incorporated herein by reference. The method disclosed in that patent includes the step of returning unused blood, that was withdrawn from the test subject and was still remaining in the catheter and associated tubing after collection, back into the animal. The injection of unused blood back into a test subject is important when the subject is a small animal, because in that instance one must be concerned with the conservation of red blood cells (erythrocytes) in the small animal. Red blood cell replenishment requires a period of 10 to 14 days in rodents, therefore a study running over a period of only 1 to 4 days is not long enough for the body to replace any blood cells removed during automated sampling. If too many red blood cells are removed, the animal is at risk of anemia and its associated complications. The return of withdrawn blood into some larger animals, such as humans, may also be needed to conserve erythrocytes if the animal is sufficiently small (e.g., human infants), but in other cases may not be desirable since returned blood would be accompanied by anti-coagulants to keep the blood from clotting while in the automated blood sampling device. Although the required concentration of an anticoagulant, such as heparin, when used in blood return, is less than 2% of the typical therapeutic dose, it may be desirable to seek an alternative approach to automated blood sampling which either does not re-inject blood into the animal being monitored, or returns blood using an alternative means of preventing coagulation of the blood while it is out of the body during connection to the automated blood sampler.
As discussed in U.S. Pat. No. 6,062,224, it is sometimes desirable to monitor the animal while it is active and/or to allow the animal to engage in various types of activity during the testing or monitoring of the animal. For example, rotational and vertical behavior in laboratory rodents is a well-established indicator of neurochemical changes occurring in the animal during testing. The clockwise or counterclockwise preference of the animal, the frequency of such rotation, and similar information concerning the vertical movement of the animal are valuable data. Accordingly, U.S. Pat. No. 6,062,224 and U.S. Pat. No. 5,816,256 disclose movement-responsive systems that include a container for housing the animal and a mechanism for rotating the container in response to rotational movement of the animal.
The devices disclosed in the above-referenced patents are very useful in monitoring small animals because these devices allow for monitoring the animal without undue interference with the movement or normal activities of the animal, and the automation eliminates the need for human handling and the stress associated with such handling. Although this same concept can be envisioned for some larger mammals (e.g. pigs), it would not be practical for all human studies. The exception would be studies in neonatal intensive care units where premature infants are not much different in weight than an average guinea pig, have similar sized veins, and are much less mobile. In the case of neonatal intensive care, a traditional incubator would be substituted for a cage, and automated blood sampling would be conducted under continuous supervision by medical personnel. The advantage of automated blood sampling in premature infants would to be alleviate the trauma associated with multiple “sticks” (insertion of a needle into a vein or artery) during the repeated blood sampling that is necessary to monitor disposition of drug treatments. These patients are highly medicated and because they have undeveloped organs for drug metabolism and excretion, the therapeutic concentration of the drugs used is highly variable. Neonates must be constantly monitored to avoid toxic reactions due to overdose. In these patients, the extremely tiny blood vessels make the process of blood sampling extremely difficult for the phlebotomist (blood sampling technician), traumatic for the patient, and emotionally challenging for the parents and all associated medical personnel.
In human studies that involve the collection of blood for Phase 1 Clinical Trials, there are several other reasons that would justify the use of automated blood sampling, and specifically a mobile device for conducting this process. For example, mobility would be useful to allow a human subject to utilize a private restroom facility without interrupting a test or monitoring session. Humans are more likely to participate in automated blood sampling studies if their movements are unrestricted, and they can move to different rooms within the clinic to eat, watch television, or engage in entertainment like card playing or board games. Automated blood sampling, as well as the automation of other tests conducted during Phase 1 Clinical Trials (such as electrocardiography, blood pressure recording, and body temperature monitoring) can potentially be done with greater temporal accuracy (i.e. the collection of samples at a specific time), and the use of less human personnel, than manual methods of acquiring the same samples and data.
Large animals, such as dogs or pigs, may not respond well to the tethering and movement-responsive caging required for operation of the 6,062,224 and 5,816,256 device. Furthermore, that device may be incompatible with an animal that is agile (monkeys, primates), or able to jump high (monkeys, dogs, rabbits). The movement-responsive cage for a strong animal (pig, horse, sheep, cow, goat) would have to be constructed of even stronger materials, increasing the cost and weight of the device. Tethering would necessarily restrict the animal's movement to the confines of the test cage and may induce test-related stress for the animal. Stress involves release of various hormones, and such hormones have a profound effect on the redirection of blood flow as well as the function of many physiological systems in the body. Therefore, the test conditions should be designed to reduce this stress effect as much as possible. It is therefore desirable to provide a system which does not unduly restrict movement of the animal, does not induce significant test related stress, is reasonable in size, can be manufactured, operated and maintained at reasonable cost, and which is adapted for larger animals including, but not limited to, pigs, cows, horses, dogs, primates, and humans.